Idarubicin for treatment of newly diagnosed acute myeloid leukaemia

Background

Acute myeloid leukaemia (AML) is a type of cancer that mainly affects bone marrow and peripheral blood. Although 40% to 45% of AML patients enjoy long-term disease-free survival, most patients will die of the disease. Induction therapy is the first phase of treatment of newly diagnosed AML which is essential for prolonging survival. An anthracycline (a class of chemotherapy drugs derived from the Streptomyces bacterium Streptomyces peucetius var. caesius) combined with cytarabine (a chemotherapy drug used mainly in treatment of haematological malignancies) has remained the standard of induction therapy for several decades. Nowadays there are several kinds of anthracyclines available, among which idarubicin (IDA) draws more attention because of its theoretical advantages in improving efficacy and reducing side effects. However, clinical trials comparing IDA with other anthracyclines have conflicting results.

Objectives

To clarify the role of IDA in induction therapy of newly diagnosed AML.

Methods

Data from available randomised controlled trials (RCTs) that compared IDA with other anthracyclines in induction therapy of newly diagnosed AML were meta-analysed. The data collected are up to 3 August 2014.

Results

Twenty-seven RCTs involving 9549 patients were included. The consolidation treatments adopted in the included studies were comparable and had no impact on the results.

Eighteen RCTs assessed IDA versus daunorubicin (DNR; a chemotherapy drug in the anthracycline family). Results showed that IDA compared to DNR prolongs overall survival and disease-free survival, increases complete remission rate, and reduces relapse rate, although increases the risks of death on induction therapy and grade 3/4 mucositis (a kind of painful inflammation and ulceration of mucous membranes lining the digestive tract). No difference in other various grade 3/4 adverse events was found.

Eight RCTs evaluated IDA versus mitoxantrone (MIT). We found no difference in overall survival, disease-free survival, complete remission rate, the risks of death on induction therapy and relapse. The risks of various grade 3/4 adverse events were also similar between arms.

Two RCTs compared IDA with doxorubicin (DOX). Results suggested that complete remission rate was improved with IDA. No difference was noted in disease-free survival and the risk of grade 3/4 cardiac toxicity.

Two other RCTs compared IDA with zorubicin (ZRB). Results suggested that the risk of grade 3/4 mucositis was lower with IDA. No difference was found for disease-free survival, complete remission rate, the risks of death on induction therapy, grade 3/4 nausea/vomiting, diarrhoea, and hepatic toxicity.

Conclusions

The currently available evidence suggests that in induction therapy of newly diagnosed AML, IDA is superior to DNR in terms of prolonging overall survival and disease-free survival, increasing complete remission rate and reducing relapse rate, although IDA may increase the risks of death on induction therapy and grade 3/4 mucositis. The current evidence does not support the superiority of IDA over MIT. There is insufficient evidence for clarifying the role of IDA versus DOX or ZRB. Additionally, there is no evidence for a difference on the effect of IDA compared with other anthracyclines (DNR, MIT, DOX and ZRB) on quality of life.

Authors' conclusions: 

Compared with DNR in induction therapy of newly diagnosed AML, IDA prolongs OS and DFS, increases CR rate and reduces relapse rate, although increases the risks of death on induction therapy and grade 3/4 mucositis. The currently available evidence does not show any difference between IDA and MIT used in induction therapy of newly diagnosed AML. There is insufficient evidence regarding IDA versus DOX and IDA versus ZRB to make final conclusions. Additionally, there is no evidence for difference on the effect of IDA compared with DNR, MIT, DOX or ZRB on QoL.

Read the full abstract...
Background: 

Anthracycline combined with cytarabine has been the standard for induction therapy of newly diagnosed acute myeloid leukaemia (AML) for several decades. Due to theoretical advantages, idarubicin (IDA) might be the most effective and tolerable anthracycline. However, there is no evidence that would definitively prove the superiority of IDA over other anthracyclines.

Objectives: 

To assess the efficacy and safety of IDA versus other anthracyclines in induction therapy of newly diagnosed AML.

Search strategy: 

We identified relevant randomised controlled trials (RCTs) by searching the Cochrane Central Register of Controlled Trials (The Cochrane Library 2014, Issue 8), MEDLINE (from 1946 to 3 August 2014), EMBASE (from 1974 to 3 August 2014), Chinese BioMedical Literature Database (1978 to 3 August 2014), relevant conference proceedings and databases of ongoing trials.

Selection criteria: 

RCTs that compared IDA with other anthracyclines in induction therapy of newly diagnosed AML.

Data collection and analysis: 

Two review authors independently extracted data and assessed the quality of studies according to methodological standards of the Cochrane Collaboration. We estimated hazard ratios (HRs) for time-to-event data outcomes using the inverse variance method, and risk ratios (RRs) for dichotomous data outcomes using the Mantel-Haenszel method. We adopted a fixed-effect model and repeated the main meta-analysis by a random-effects model in a sensitivity analysis.

Main results: 

We identified 2017 references. Ultimately, 27 RCTs (including 22 two-armed RCTs and five three-armed RCTs) involving 9549 patients were eligible. The consolidation treatments adopted in the studies were comparable and had no impact on the results. Overall, the risk of bias of the studies was unclear to high.

Eighteen RCTs (N = 6755) assessed IDA versus daunorubicin (DNR). The main meta-analyses showed that IDA compared with DNR prolonged overall survival (OS) (12 studies, 5976 patients; HR 0.90, 95% confidence interval (CI) 0.84 to 0.96, P = 0.0008; high quality of evidence) and disease-free survival (DFS) (eight studies, 3070 patients; HR 0.88, 95% CI 0.81 to 0.96, P = 0.004; moderate quality of evidence), increased complete remission (CR) rate (18 studies, 6692 patients; RR 1.04, 95% CI 1.01 to 1.07, P = 0.009; moderate quality of evidence), and reduced relapse rate (four studies, 1091 patients; RR 0.88, 95% CI 0.80 to 0.98, P = 0.02; moderate quality of evidence), although increased the risks of death on induction therapy (14 studies, 6349 patients; RR 1.18, 95% CI 1.01 to 1.36, P = 0.03; moderate quality of evidence) and grade 3/4 mucositis (five studies, 2000 patients; RR 1.22, 95% CI 1.04 to 1.44, P = 0.02; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (six studies, 2795 patients; RR 0.98, 95% CI 0.70 to 1.37, P = 0.91; moderate quality of evidence) and other grade 3/4 adverse events (AEs). None of the studies reported on quality of life (QoL).

Eight RCTs (N = 2419) evaluated IDA versus mitoxantrone (MIT). The main meta-analyses showed that there was no evidence for difference between arms in OS (six studies, 2171 patients; HR 0.98, 95% CI 0.89 to 1.08, P = 0.69; high quality of evidence), DFS (four studies, 249 patients; HR 0.88, 95% CI 0.70 to 1.10, P = 0.26; low quality of evidence), CR rate (eight studies, 2411 patients; RR 0.97, 95% CI 0.92 to 1.03, P = 0.32; moderate quality of evidence), the risks of death on induction therapy (five studies, 2055 patients; RR 1.10, 95% CI 0.88 to 1.38, P = 0.39; moderate quality of evidence) and relapse (three studies, 328 patients; RR 0.99, 95% CI 0.80 to 1.22, P = 0.89; moderate quality of evidence). There was no evidence for difference in the risks of grade 3/4 cardiac toxicity (one study, 160 patients; RR 0.67, 95% CI 0.11 to 3.88, P = 0.65; low quality of evidence) and other grade 3/4 AEs. None of the studies reported on QoL.

Two RCTs (N = 211) compared IDA with doxorubicin (DOX). Neither study assessed OS. One study showed that there was no evidence for difference in DFS (63 patients; HR 0.62, 95% CI 0.34 to 1.14, P = 0.12; low quality of evidence). The main meta-analysis for CR rate showed an improved CR rate with IDA (two studies, 187 patients; RR 1.28, 95% CI 1.03 to 1.59, P = 0.02; low quality of evidence). Neither study provided data for the risks of death on induction therapy and relapse. One trial showed that there was no evidence for difference in the risk of grade 3/4 cardiac toxicity (one study, 100 patients; RR 0.31, 95% CI 0.01 to 7.39, P = 0.47; very low quality of evidence). Neither study reported on QoL.

Two RCTs (N = 1037) evaluated IDA versus zorubicin (ZRB). Neither study assessed OS. One trial showed that there was no evidence for difference in DFS (one study, 155 patients; HR 1.25, 95% CI 0.83 to 1.88, P = 0.29; low quality of evidence). The main meta-analyses for CR and death on induction therapy both showed that there was no evidence for difference (CR rate: two studies, 964 patients; RR 1.04, 95% CI 0.96 to 1.13, P = 0.31; low quality of evidence. risk of death on induction therapy: two studies, 964 patients; RR 0.75, 95% CI 0.50 to 1.13, P = 0.17; moderate quality of evidence). Neither study reported the risks of relapse and grade 3/4 cardiotoxicity. One trial showed that IDA reduced the risk of grade 3/4 mucositis. Neither study reported on QoL.

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